Biodegradable metallic micro-structures.

ABSTRACT

Bioresorbable medical devices, such as stents, scaffolds and other medical devices implantable in human and animal bodies, in which galvanic couples are formed. The devices include bioresorbable amalgamates, wires, laminates, layered structures or combinations thereof. Also, methods of manufacturing the devices, including laminating, folding, 110 braiding, weaving, crocheting or cold spraying of materials with different galvanic potentials Also, machining of amalgamated materials using electrical discharge machining.

The present application is a continuation-in-part of U.S. patent application Ser. No. 16/015,461 filed Jun. 22, 2018, which is a continuation-in-part of U.S. patent application Ser. No. 14/398,521 filed Mar. 11, 2014, now issued as U.S. Pat. No. 10,028,847, which is a national phase entry of PCT application PCT/CA2013/000445, filed May 2, 2013, which claimed priority from U.S. provisional patent application Ser. No. 61/641,398 filed May 2, 2012. The contents of all these patent applications is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to the field of medicine and is more particularly concerned with biodegradable temporary structures such as stents, membranes, mesh, clips, sutures and implants.

BACKGROUND

Obstructive coronary diseases may be caused by a stable or an unstable plaque. An unstable atherosclerotic plaque is vulnerable to rupture and to subsequent thrombogenic reaction, which can lead to sudden death. In general, when the associated stenosis of a stable plaque reaches a certain threshold, it may cause a lack of myocardium perfusion and associated chest pain or angina pectoris.

Historically, the first endovascular mechanical treatment was introduced in 1977 by Andreas Gruentzig who introduced the angioplasty balloon. Percutaneous angioplasty was however associated with a phenomenon called restenosis. Restenosis is essentially the re-obstruction of the vessel caused by vessel recoil, remodeling and hyperplasia. In order to treat the acute recoil and limit the restenosis process, Palmaz-Schatz introduced a new medical implant, the stent, in 1986. A new phenomenon was then observed, in-stent restenosis, or the re-obstruction inside the stent. However, the restenosis rates associated with balloon angioplasty (40-60%) were greatly improved with the advent of stents in 1986 (20-30%) which nevertheless still constitutes a relatively high rate. In order to treat the in-stent restenosis process, Drug Eluting Stents (DES) were introduced. DES were initially coated with antiproliferative and anti-thrombotic compounds. The first DES (Cypher, Cordis) was approved in Europe in 2002. DES initially were effective in limiting restenosis with reported rates between 0 and 16%. However, a few years following their introduction, a serious phenomenon was reported. Late thrombosis (reported by Camenzin on the “Black Sunday” in 2006) was demonstrated to be associated with DES. It was subsequently shown that the rate of late thrombosis continues to increase with time following the implantation. This is phenomenon is of great concern since thrombosis is a life threatening event possibly leading to myocardium infarction.

The causes of late thrombosis are not fully elucidated but processes like chemical compound effect, chronic inflammation and vessel wall injury are reported in the literature. Concerning chronic inflammation and vessel wall injury, a direct link was demonstrated between stent fracture and In-Stent Restenosis (ISR) and thrombosis. ISR is observed both with bare metal stents (BMS) and DES with respective rates of 20-25% and 0-16.7%. The relation with DES fracture was shown to be more frequent than previously thought. The reason is that most of the time stent fracture is clinically silent. However, with imaging modalities, the reported incidence is 1-2% and pathologic investigations reported an incidence of 29% with about 5% associated with adverse effects: inflammation, ulceration, avulsion, ISR, thrombosis.

Furthermore, it was also shown that stent fractures are correlated with anatomical location (tortuosity), with stent fractures more common in the Right Coronary Artery (RCA) with a rate of 57% than in the Left Anterior Descending (LAD) with a rate of 34%, and stent design and lesion types. In addition, stress fractures are also strongly correlated with time: stents may get fully broken over long periods of time. For example, a few broken struts have been reported after implantation times of about 172 d and full stent fracture after implantation times of 1800 d.

This problem is inherently a mechanical problem linked to the notion of fatigue of material. Every material subjected to cyclic loading, such as heart beats, will fatigue and eventually fail. Possible solutions for stent design include developing a superior material for manufacturing the stent for higher longevity and biodegradable stents. Indeed, a biodegradable stent would essentially disappear once it has performed its temporary scaffolding task and thus avoid being subjected to cyclic fatigue.

It is with this perspective that the lgaki-Tamai stent, the first polymeric biodegradable stent made of poly-L-lactide polymer, was introduced in 2003. Since polymers have mechanical properties that are about 2 orders of magnitude lower than metals, mechanical integrity problems were reported, including acute recoil. Given their relative weaker mechanical properties, larger struts are required to ensure proper scaffolding of the vascular wall. The thicker struts, in turn, may cause more resistance to blood flow and may be too large to implant in many blood vessels. Their capacity to properly scaffold plaques with calcification was also mentioned. In addition, larger struts were also associated with more vessel injuries, thus potentially leading to more vessel response and hyperplasia.

At about the same time, biodegradable metallic stents were investigated. The principle was to exploit the property of reactive metals to corrode for biodegradation. The initial selected metal was magnesium. The concept of biodegradation has been shown to work. However, there are several limitations associated with the use of magnesium (WE magnesium). Similarly to polymers, magnesium has mechanical properties that are much lower than the current super alloys used for commercial stents (such as 316L stainless steel, L605 cobalt-chromium alloy). As a consequence, thicker struts are also required, and these are associated with the same problems of possible flow disturbances and wall injury. Indeed, negative remodelling was recently demonstrated with the use of the magnesium-based stent.

More recently, other reactive metal alloys were investigated, including iron-manganese alloys and electroformed iron. These alloys have relatively better mechanical strength than magnesium-based alloys. However, the iron-manganese alloys have quite large metallic grains (100 microns), which is an issue given that a stent strut dimension is below 100 microns. Electroformed irons have much smaller grain sizes (2-8 microns) but have limited ductility. Furthermore, control of the degradation rate of these alloys is a challenging task.

Some stents, such as the stent proposed in US Pat. No. 8,080,055 by Atanasoska et al. and issued Dec. 20, 2011, use galvanic corrosion between a core of a stent and a coating made of a different material to promote degradation of the stent in situ. However, such stents require thick struts having a layered structure. This structure also results in heterogeneous degradation as the cathodic layers will remain uncorroded and the anodic layer will also degrade non-homogeneously.

Accordingly, there is a need in the industry to provide an improved bioresorbable stent and other bioresorbable medical devices, along with methods of manufacturing such medical devices. An object of the present invention is therefore to provide such devices and methods.

SUMMARY OF THE INVENTION

In a broad aspect, the invention provides a bioresorbable stent, the bioresorbable stent comprising: a bioresorbable material, the bioresorbable material being an intermixed particulate material including cathodic particles and anodic particles bound to each other. The anodic particles are made of an anodic material and the cathodic particles are made of a cathodic material, the anodic and cathodic materials forming a galvanic couple with the anodic material being electropositive and the cathodic material being electronegative. The anodic and cathodic particles are present in a predetermined ratio in the bioresorbable material. The anodic particles, cathodic particles and predetermined ratio are such that bioresorption of the stent is promoted by galvanic corrosion between the anodic and cathodic materials.

For the purpose of this document, the terminology “stent” refers to structures to be used during medical interventions, on humans or animals, to maintain open or to open a cavity in biological tissues. For example, a stent could be used, among other uses, to maintain an artery open. Stents therefore also include devices referred to in the current literature as “scaffolds”.

In some embodiments, the cathodic and anodic particles are substantially homogeneously dispersed in the bioresorbable material.

In some embodiments, the anodic and cathodic materials are metallic.

Typically, the anodic and cathodic materials are biocompatible.

In some embodiments, the anodic material is selected from the group consisting of iron, iron alloys and vanadium and the cathodic material is selected from the group consisting of cobalt-chromium alloys, stainless steel, tantalum, titanium and platinum-steels.

In some embodiments, the anodic material and cathodic material are selected from the group of couples consisting of iron/stainless steel and iron/tantalum.

In some embodiments, the anodic and cathodic particles are from about 1 μm to about 30 μm in average size.

In some embodiments, the stent is bioresorbable at a predetermined rate; and the anodic particles, cathodic particles and predetermined ratio are selected such that the stent is bioresorbable at the predetermined rate due to galvanic corrosion between the anodic and cathodic materials.

In some embodiments, the bioresorbable material further includes rate control particles made of a rate control material and dispersed in the bioresorbable material; and the rate control particles affect the galvanic corrosion to change the predetermined rate in accordance with a predetermined rate change.

In some embodiments, the rate control particles increase the predetermined rate. In other embodiments, the rate control particles decrease the predetermined rate. For example, the rate control material is selected from the group consisting of: salts, acids, solid electrolytes, ceramics, dielectrics and metal oxides.

In some embodiments, the bioresorbable material is an annealed material.

In some embodiments, the anodic and cathodic particles include grains of about 1 μm or less in average size. In some embodiments, the anodic and cathodic particles include grains of about 4 μm or less in average size. In some embodiments, the anodic and cathodic particles include grains of about 10 μm or less in average size.

In some embodiments, the anodic and cathodic materials have bulk specific weights that differ by about 50% or less. In some embodiments, the anodic and cathodic materials have bulk specific weights that differ by about 20% or less.

In some embodiments, the anodic and cathodic materials have hardnesses that differ by about 50% or less. In some embodiments, the anodic and cathodic materials have hardnesses that differ by about 20% or less.

In some embodiments, the predetermined ratio is about 4:1 w/w (weight to weight) or more in the anodic particles with respect to the cathodic particles. In some embodiments, the predetermined ratio is about 8:1 w/w or more in the anodic particles with respect to the cathodic particles. In some embodiments, the predetermined ratio is about 20:1 w/w or more in the anodic particles with respect to the cathodic particles.

In some embodiments, the cathodic material is stainless steel and the anodic material is iron.

In some embodiments, the bioresorbable material is substantially non-porous. For example, the bioresorbable material has a porosity of about 0.2% or less.

In some embodiments, the stent is entirely made of the bioresorbable material. In other embodiments, the stent further comprises a non-bioresorbable portion.

In another broad aspect, the invention provides a method for manufacturing a bioresorbable stent, the method comprising: providing an anodic powder including anodic particles made of an anodic material; providing a cathodic powder including cathodic particles made of a cathodic material, the anodic and cathodic materials forming a galvanic couple; mixing the anodic and cathodic powders together in a predetermined ratio to obtain a mixed powder; cold spraying the mixed powder on a substrate to obtain a bioresorbable material; and processing the bioresorbable material to form the bioresorbable stent. The anodic particles, cathodic particles and predetermined ratio are selected so that bioresorption of the stent is promoted by galvanic corrosion between the anodic and cathodic materials.

The specific details regarding some embodiments of the stent described hereinabove apply to the present method.

In some embodiments, the method further comprises providing a bioresorption rate control powder including rate control particles made of a rate control material. Mixing the anodic and cathodic powders together includes also mixing a rate control quantity of the bioresorption rate control powder with the anodic and cathodic powders to obtain the mixed powder. The bioresorption rate control powder affects the galvanic corrosion to change the predetermined rate in accordance with a predetermined rate change.

In some embodiments, the substrate has a substantially planar form, or cylindrical form, or thick plate form, or thin sheet form.

In some embodiments, processing the bioresorbable material to form the bioresorbable stent includes taking a slice of a predetermined thickness of the bioresorbable material and shaping the slice to form the bioresorbable stent, the slice including substantially opposed slice first and second side edges.

In some embodiments, taking the slice of the predetermined thickness of the bioresorbable material includes cutting the slice with electrical discharge machining methods (EDM). The EDM methods can be also used to cut the shape of the final stent blank in a tubular form.

In some embodiments, processing the bioabsorbable material to form the tubular stent blanks includes CNC machining methods such as CNC Turning operations or CNC Milling operations.

In some embodiments, taking the slice of the predetermined thickness of the bioresorbable material includes cutting the slice with electrical discharge machining methods (EDM). The EDM methods can be also used to cut the shape of the final stent blank in a tubular form.

In some embodiments, shaping the slice includes folding the slice to form a cylinder so that the slice first and second side edges are substantially adjacent to each other and welding the slice first and second side edges to each other.

In some embodiments, shaping the slice includes embossing the slice to form a half-cylinder and welding a similar half-cylinder thereto to form a complete cylinder.

In some embodiments, shaping the slice to form the stent includes forming a substantially cylindrical stent blank and cutting out portions of the stent blank to define stent struts.

In some embodiments, cutting out portions of the stent blank includes laser cutting the portions of the stent blank under conditions maintaining the stent blank under an annealing temperature of the anodic and cathodic materials.

In some embodiments, cutting out portions of the stent blank includes laser cutting the portions of the stent blank using picosecond or femtosecond laser equipment.

In some embodiments, the method further comprises annealing the bioresorbable material.

In some embodiments, the bioresorbable material is annealed under conditions resulting in grains of the anodic and cathodic materials in the anodic and cathodic particles to remain below about 1 μm in average size. In some embodiments, the bioresorbable material is annealed under conditions resulting in grains of the anodic and cathodic materials in the anodic and cathodic particles to remain below about 4 μm in average size. In some embodiments, the bioresorbable material is annealed under conditions resulting in grains of the anodic and cathodic materials in the anodic and cathodic particles to remain below about 10 μm in average size. In some embodiments, the bioresorbable material is dynamically annealed. In some embodiments, the bioresorbable material is annealed at a temperature between 70% and 90% of a melting temperature of a lowest melting temperature material selected from the anodic and cathodic materials.

In some embodiments, the substrate is substantially planar and processing the bioresorbable material to form the bioresorbable stent includes cutting a cylinder in the bioresorbable material and emptying the cylinder to form a stent blank.

In yet another broad aspect, the invention provides a bioresorbable material, the bioresorbable material being an intermixed particulate material comprising cathodic particles and anodic particles bound to each other. The anodic particles are made of an anodic material and the cathodic particles are made of a cathodic material, the anodic and cathodic materials forming a galvanic couple. The anodic and cathodic particles are present in a predetermined ratio in the bioresorbable material. The anodic particles, cathodic particles and predetermined ratio are such that bioresorption of the bioresorbable material is promoted by galvanic corrosion between the anodic and cathodic materials.

The specific details regarding some embodiments of the stent and the bioresorbable material from which the stent is made as described hereinabove, apply to some embodiments of the present bioresorbable material.

In yet another broad aspect, the invention provides an intermixed particulate material comprising: cathodic particles and anodic particles bound to each other, the anodic particles being made of an anodic material and the cathodic particles being made of a cathodic material, the anodic and cathodic materials forming a galvanic couple.

The specific details regarding some embodiments of the stent and the bioresorbable material from which the stent is made, as described hereinabove, apply to some embodiments of the present particulate material.

In yet another broad aspect, the invention provides a method for manufacturing an intermixed particulate material, the method comprising: providing an anodic powder including anodic particles made of an anodic material; providing a cathodic powder including cathodic particles made of a cathodic material, the anodic and cathodic materials forming a galvanic couple; mixing the anodic and cathodic powders together in a predetermined ratio to obtain a mixed powder; and cold spraying the mixed powder on a substrate to obtain the intermixed particulate material.

The specific details regarding some embodiments of the stent and the bioresorbable material from which the stent is made, as described hereinabove, apply to some embodiments of the present method.

In yet another broad aspect, the invention provides a method for manufacturing a bioresorbable medical device, the method comprising: providing an anodic powder including anodic particles made of an anodic material; providing a cathodic powder including cathodic particles made of a cathodic material, the anodic and cathodic materials forming a galvanic couple; mixing the anodic and cathodic powders together in a predetermined ratio to obtain a mixed powder; cold spraying the mixed powder on a substrate to obtain a bioresorbable material; and processing the bioresorbable material to form the bioresorbable medical device. The anodic particles, cathodic particles and predetermined ratio are such that bioresorption of the stent is promoted by galvanic corrosion between the anodic and cathodic materials.

The specific details regarding some embodiments of the stent and the bioresorbable material from which the stent is made, as described hereinabove, apply to some embodiments of the present method.

In some embodiments, the medical device is selected from the group consisting of stents, scaffolds, markers, anchors, clips, occluders, sutures, surgical devices and orthopedic support devices.

In yet another broad aspect, the invention provides a method of implanting a bioresorbable stent in a patient, the method comprising: determining a desired resorption rate of the bioresorbable stent based on the satisfaction of predetermined criteria by the patient; selecting a patient stent from a set of predetermined stents, the predetermined stents being as defined above, the patient stent having the desired resorption rate when implanted in the patient; and implanting the patient stent in the patient. In some embodiments, the method further comprises resorbing the stent in the patient at the desired resorption rate.

Advantageously, in some embodiments of the invention, a relatively small bioresorbable stent that is nevertheless strong and ductile enough can be manufactured using the proposed material.

In yet another broad aspect, there is provided a method for manufacturing a bioresorbable stent, the method comprising: providing a mixed powder including anodic particles made of a metallic anodic material and cathodic particles made of a metallic cathodic material, the anodic and cathodic materials forming a galvanic couple; cold spraying the mixed powder on a substrate to obtain an amalgamated material; forming a substantially tubular stent blank made of the amalgamated material by machining the amalgamated material using electrical discharge machining (EDM); removing selected portion of the stent blank to form the stent; wherein the anodic particles, cathodic particles and predetermined ratio are selected so that bioresorption of the stent is promoted by galvanic corrosion between the anodic and cathodic materials.

The material formed through cold-spray is an amalgamated material in which the various particles contained in the mixed powder have been amalgamated, or in other words stuck to each other, using cold spraying.

There may be provided a method further comprising removing the amalgamated material from the substrate and annealing the amalgamated material removed from the substrate before forming the stent blank.

There may be provided a method wherein the amalgamated material is annealed under conditions resulting in grains of the anodic and cathodic materials in the anodic and cathodic particles to remain below about 1 μm in average size.

There may be provided a method wherein the amalgamated material is annealed under conditions resulting in grains of the anodic and cathodic materials in the anodic and cathodic particles to remain below about 4 μm in average size.

There may be provided a method wherein the amalgamated material is annealed under conditions resulting in grains of the anodic and cathodic materials in the anodic and cathodic particles to remain below about 10 μm in average size.

There may be provided a method wherein the amalgamated material is annealed at a temperature below a sintering temperature of the amalgamated material.

There may be provided a method wherein the amalgamated material is annealed at a temperature between 70% and 90% of a melting temperature of a lowest melting temperature material selected from the anodic and cathodic materials.

There may be provided a method wherein the cathodic material is stainless steel and the anodic material is iron.

There may be provided a method wherein the amalgamated material is annealed at an annealing temperature of between 800° C. and 1400° C. for an annealing duration of 30 minutes to 4 hours.

There may be provided a method wherein the annealing temperature is between 1100° C. and 1300° C. and the annealing duration is between 1 and 3 hours.

There may be provided a method wherein the amalgamated material is brought from room temperature to the annealing temperature at a predetermined heating rate.

There may be provided a method wherein the predetermined heating rate is between about 100 and about 400° C./hr.

There may be provided a method wherein the amalgamated material is brought from annealing temperature to the room temperature at a predetermined cooling rate.

There may be provided a method wherein the predetermined cooling rate is between about 100 and about 400° C./hr.

There may be provided a method wherein the anodic material is selected from the group consisting of iron, iron alloys and vanadium and the cathodic material is selected from the group consisting of cobalt-chromium alloys, stainless steel, tantalum, titanium and platinum-steels.

There may be provided a method wherein the anodic material and cathodic material are selected from the group of couples consisting of iron/stainless steel and iron/tantalum.

There may be provided a method wherein the stent blank defines a longitudinally extending stent passageway, the stent passageway being formed in the amalgamated material before a peripheral surface of the stent blank is machined.

There may be provided a method wherein forming the stent passageway includes forming a pilot hole in the amalgamated material, inserting an EDM wire in the pilot hole, and enlarging the pilot hole to a predetermined diameter using wire EDM.

There may be provided a method wherein the anodic and cathodic particles are from about 1 μm to about 30 μm in average size.

There may be provided a method wherein the anodic and cathodic particles include grains of about 1 μm or less in average size.

There may be provided a method wherein the anodic and cathodic particles include grains of about 4 μm or less in average size.

There may be provided a method wherein the anodic and cathodic particles include grains of about 10 μm or less in average size.

There may be provided a method wherein the anodic and cathodic materials have bulk specific weights that differ by about 50% or less.

There may be provided a method wherein the anodic and cathodic materials have bulk specific weights that differ by about 20% or less.

There may be provided a method wherein the anodic and cathodic materials have hardnesses that differ by about 50% or less.

There may be provided a method wherein the anodic and cathodic materials have hardnesses that differ by about 20% or less.

There may be provided a method wherein the predetermined ratio is about 4:1 w/w or more in the anodic particles with respect to the cathodic particles.

There may be provided a method wherein the predetermined ratio is about 8:1 w/w or more in the anodic particles with respect to the cathodic particles.

There may be provided a method wherein the predetermined ratio is about 20:1 w/w or more in the anodic particles with respect to the cathodic particles.

There may be provided a method wherein the mixed powder includes rate control particles made of a rate control material, the rate control material affecting the galvanic corrosion to change the predetermined rate in accordance with a predetermined rate change.

There may be provided a method wherein the bioresorption rate control powder increases the predetermined rate.

There may be provided a method wherein the bioresorption rate control powder decreases the predetermined rate.

There may be provided a method wherein the rate control material is selected from the group consisting of: salts, acids, solid electrolytes, ceramics, dielectrics and metal oxides.

There may be provided a method wherein the EDM is performed with the amalgamated material immersed in an oil-based dielectric fluid. The oil-based dielectric fluid is a fluid that will not promote corrosion of the amalgamated material.

There may be provided a method wherein the oil-based dielectric fluid is actively circulated to promote heat removal from the amalgamated material during machining.

In yet other embodiments, bioresorbable stents are manufactured from wires or stacked and folded sheets of material including a mix of anodic and galvanic material building elements. For example, a wire or set of wires may be braided or twisted together using smaller filaments of an anodic material and filaments of a cathodic material. Such wires can then be used to manufacture wire stents and other medical devices. Braiding is performed so that the cathodic and anodic material are in contact with each other at multiple locations there along with specific and predetermined alternating of the filaments. Such a wire or individual filaments may be used to make a bioresorbable fabric. In other embodiments, thin foils or cathodic and anodic materials are stacked and bonded to each other. Folding the foils allows to the anodic and cathodic alternation to make bioresorbable structures.

In yet another broad aspect, the invention provides a bioresorbable stent, comprising: an anodic material in filament form and a cathodic material in filament form, the anodic and cathodic materials being metallic and forming a galvanic couple, the anodic and cathodic materials being distributed in the stent so that the anodic and cathodic materials contact each other at a plurality of junctions; wherein bioresorption of the stent is promoted by galvanic corrosion between the anodic and cathodic materials at the junctions.

There may also be provided a bioresorbable stent wherein at least one anodic filament made of the anodic material and at least one cathodic filament made of the cathodic material are braided together in a wire, the wire including at least some of the plurality of junctions.

There may also be provided a bioresorbable stent wherein the anodic and cathodic filaments are also braided with a carrier filament.

There may also be provided a bioresorbable stent wherein the carrier filament is metallic.

There may also be provided a bioresorbable stent wherein the carrier filament is made of a material that differs from the anodic and cathodic materials.

There may also be provided a bioresorbable stent wherein the anodic and cathodic filaments have different pitches relative to the wire.

There may also be provided a bioresorbable stent wherein the bioresorbable stent is a wire stent made of one or more of the wires.

There may also be provided a bioresorbable stent wherein a plurality of anodic filament segments made of the anodic material and a plurality of cathodic filament segments made of the cathodic material are weaved together in a fabric, the fabric including at least some of the plurality of junctions.

There may also be provided a bioresorbable stent wherein the anodic filament segments are substantially parallel to each other in the fabric and the cathodic filament segments are substantially parallel to each other in the fabric, the anodic filament segment being substantially perpendicular to the cathodic filament segments.

There may also be provided a bioresorbable stent wherein one of the anodic and cathodic materials forms a base grid defining a plurality of grid apertures and another one of the anodic and cathodic materials is crocheted into the base grid through the apertures.

There may also be provided a bioresorbable stent wherein at least one of the cathodic and anodic materials are in beaded filament form.

There may also be provided a bioresorbable stent wherein both the cathodic and anodic materials are in beaded filament form.

There may also be provided a bioresorbable stent wherein the cathodic and anodic filaments are under tension and the junctions are created due to normal forces between the filaments at locations where the filaments intersect.

There may also be provided a bioresorbable stent wherein the cathodic and anodic materials are sintered to each other.

There may also be provided a bioresorbable stent wherein the anodic material is selected from the group consisting of iron, iron alloys, mild steel and vanadium and the cathodic material is selected from the group consisting of cobalt-chromium alloys, stainless steel, mild steel, tantalum, titanium and platinum-steels.

There may also be provided a bioresorbable stent wherein the anodic material and cathodic material are selected from the group of couples consisting of iron/stainless steel, two different mild steels and iron/tantalum.

There may also be provided a bioresorbable stent wherein the cathodic and anodic materials have different diameters.

There may also be provided a bioresorbable stent wherein a total length of the anodic material in the bioresorbable stent differs from a total length of the cathodic material in the bioresorbable stent.

In yet another broad aspect, there is provided a bioresorbable stent, comprising a plurality of layers alternating between cathodic layers and anodic layers forming alternating galvanic couples promoting galvanic corrosion between the anodic and cathodic layers.

There may also be provided a bioresorbable stent wherein all the cathodic layers are made of a same cathodic material and all the anodic layers are made of a same anodic material, the anodic and cathodic materials forming a galvanic couple.

There may also be provided a bioresorbable stent wherein the anodic material is selected from the group consisting of iron, iron alloys, mild steel and vanadium and the cathodic material is selected from the group consisting of cobalt-chromium alloys, stainless steel, mild steel, tantalum, titanium and platinum-steels.

There may also be provided a bioresorbable stent wherein the anodic material and cathodic material are selected from the group of couples consisting of iron/stainless steel, two mild steels of different compositions and iron/tantalum.

There may also be provided a bioresorbable stent wherein the anodic layers are thinner than the cathodic layers.

There may also be provided a bioresorbable stent wherein the anodic layers are thicker than the cathodic layers.

There may also be provided a bioresorbable stent wherein the anodic layers and cathodic layers define concentric cylindrical layers.

There may also be provided a bioresorbable stent wherein the anodic layers are formed by a cathodic spiralling sheet made of the cathodic material an the anodic layers are formed by an anodic spiralling sheet made of the anodic material and parallel to the cathodic spiralling sheet.

There may also be provided a bioresorbable stent wherein the cathodic material includes a plasma deposited layer deposited the anodic material.

There may also be provided a bioresorbable stent wherein the anodic material includes a plasma deposited layer deposited the cathodic material.

In yet another broad aspect, there is provided a method of manufacturing a bioresorbable wire, the method comprising braiding together at least two metallic filaments having different galvanic potentials. For example, the two filaments are different mild steels.

Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of preferred embodiments thereof, given by way of example only and in relation with the following Figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1, in a flow chart, illustrates a method for manufacturing a stent in accordance with an embodiment of the present invention;

FIGS. 2A to 2C, in photographs, illustrate a stent manufactured using the method of FIG. 1;

FIG. 3, in an X-Y graph, illustrates mass loss per unit area for iron/stainless steel samples made in accordance with the method of FIG. 1 for pure iron (FE), pure stainless steel (316L alloy) and various mixtures of iron and stainless steel;

FIG. 4, in an X-Y graph, illustrates corrosion rate obtained from the data shown in FIG. 3;

FIG. 5, in an X-Y graph, illustrates polarization curves used to determine in an alternative manner the corrosion rate for the samples used to obtain the data presented in FIGS. 3 and 4;

FIG. 6, in an Electron BackScatter Diffraction (EBSD) Euler angle map, illustrates the microstructure of the material used to manufacture the stent of FIG. 2;

FIG. 7A, in a schematic view, illustrates a step in manufacturing a stent in accordance with an embodiment of the present invention;

FIG. 7B, in a schematic view, illustrates another step in manufacturing a stent in accordance with an embodiment of the present invention;

FIG. 7C, in a schematic view, illustrates yet another step in manufacturing a stent in accordance with an embodiment of the present invention;

FIG. 7D, in a schematic view, illustrates yet another step in manufacturing a stent in accordance with an embodiment of the present invention;

FIG. 7E, in a schematic view, illustrates yet another step in manufacturing a stent in accordance with an embodiment of the present invention;

FIG. 7F, in a schematic view, illustrates yet another step in manufacturing a stent in accordance with an embodiment of the present invention;

FIG. 7G, in a schematic view, illustrates yet another step in manufacturing a stent in accordance with an embodiment of the present invention;

FIG. 7H, in a schematic view, illustrates yet another step in manufacturing a stent in accordance with an embodiment of the present invention;

FIG. 8, in a schematic form, illustrates braiding of filaments having different compositions to manufacture a bioresorbable wire;

FIG. 9, in a schematic view, illustrates braiding of filaments to manufacture a bioresorbable wire;

FIG. 10A, in a schematic form, illustrates a sheet usable to manufacture a stent blank;

FIG. 10B, in a schematic form, illustrates the sheet of FIG. 10A curved to manufacture a stent blank;

FIG. 10C, in a schematic form, illustrates the sheet of FIG. 10A forming a cylindrical stent blank;

FIG. 10D, in a schematic form, illustrates a stent blank formed from many sheets of FIG. 10A superposed in concentric cylinders;

FIG. 10E, in a schematic form, illustrates a stent blank formed by spiralling the sheet of FIG. 10A onto itself;

FIG. 11, in a schematic view, illustrates a weaving with two different metallic wires;

FIG. 12, in a schematic view, illustrates a beaded filament;

FIG. 13, in a schematic view, illustrates crocheting of two different metallic materials;

FIG. 14, in a schematic form, illustrates lamination of two sheets having different compositions to form a bioresorbable laminate;

FIG. 15A, in a schematic form, illustrates a manner of flowing the bioresorbable laminate of FIG. 14;

FIG. 15B, in a schematic form, illustrates an alternative manner of flowing the bioresorbable laminate of FIG. 14;

FIG. 15C, in a schematic form, illustrates another alternative manner of flowing the bioresorbable laminate of FIG. 14;

FIG. 15D, in a schematic form, illustrates yet another alternative manner of flowing the bioresorbable laminate of FIG. 14;

FIG. 15E, in a schematic form, illustrates yet another alternative manner of flowing the bioresorbable laminate of FIG. 14; and

FIG. 15F, in a schematic form, illustrates yet another alternative manner of flowing the bioresorbable laminate of FIG. 14.

DETAILED DESCRIPTION

The present invention relates to novel materials and to bioresorbable, or biodegradable, medical devices including this material. Also, as detailed hereinbelow, methods of manufacturing the materials and medical devices are provided. While the following description mostly refers to a stent manufactured using the proposed material, it is within the scope of the invention to manufacture any suitable medical device using this material, such as, for example, orthopedic devices used as temporary support while tissues heal. Also, while the proposed material is well suited to the manufacture of bioresorbable medical devices, any other medical devices can be manufactured using the proposed material. Finally, while specific methods of manufacturing the proposed medical devices is proposed, in an alternative embodiment of the invention, the medical devices are manufactured using any other suitable method.

Returning to the specific case of a stent, the ideal mechanical properties for stent design are: high Elastic modulus E (to limit stent recoil), low yield strength S_(y) (to lower balloon pressure for stent expansion), high ultimate strength S_(UT) (for stent longevity), high ductility (for stent longevity and the capacity to withstand deformation under heart pulsation), a high value of the equation E·t³ (for buckling resistance, t being the strut thickness) and the capacity of the stent to withstand a sufficiently large number of cycles.

It is in order to alleviate the limitations mentioned above in the background section that the proposed invention is put forward. One objective was to develop a bioresorbable stent with a new material having a small grain size, the highest possible ductility, high strength and a controllable degradation rate.

Small grain size is advantageous given the size of the stent struts and to avoid a discontinuous material and stress concentration at the interface of grains. It should be noted that grain size should not be confused with particle size, as the proposed material is particulate. The material is made of particles, and the particles each include a plurality of grains. It is also known that for a given material, small grain sizes favor strength and fatigue resistance (basically linked to the Hall-Petch effect: strength ˜1/d^(1/2) with d the grain size). Apart from increasing strength and fatigue resistance, a smaller grain size has a definite advantage in wear properties. Stents and other medical devices may thus benefit from a significant reduction in grain size. To achieve this result, a cold spray process is proposed to manufacture the novel material.

Indeed, conventional techniques to reduce the grain size, such as cold work, usually make the material too brittle. We propose using the cold gas-dynamic spraying (CGDS) process, referred herein as “cold spray”, to generate improved materials with smaller grain sizes. The cold spray process essentially uses the energy stored in a high pressure gas to propel ultra-fine powder (nano-powder) particles at supersonic velocities (300-1500 m/s). The compressed gas is preheated (to a temperature lower than the powder melting temperature) and exits through a nozzle at high velocity. The compressed gas is also fed to a powder feeder which introduces the ultrafine powder in the gas stream jet. The nano-structured powder impacts with a substrate and the particles deform and adhere to form a coating on the substrate. The particles remain relatively cold and retain their submicron to micron range dimensions. No melting is observed and, interestingly, particles flow and mix under very high strain rates generating complex microstructures. Therefore, unwanted effects of high temperatures, such as oxidation, grain growth and thermal stresses, are absent.

The proposed material achieves bioresorption through the use of a mixture of two powders in the manufacturing process. More specifically, the bioresorbable material is an intermixed particulate material comprising cathodic particles and anodic particles bound, or amalgamated, to each other. The anodic particles are made of an anodic material and the cathodic particles are made of a cathodic material, the anodic and cathodic materials forming a galvanic couple, the anodic material being electropositive relative to the cathodic material, which is therefore electronegative. The anodic and cathodic particles are present in a predetermined ratio in the bioresorbable material. The anodic particles, cathodic particles and predetermined ratio are such that bioresorption of the stent is promoted by galvanic corrosion between the anodic and cathodic materials. Also, conventional passive oxidation of the cathode and anode occurs, which further enhances bioresorption.

In some embodiments, the proposed material and medical devices are made entirely of the cold-sprayed material, that is the bioresorbable material. Therefore, in opposition to some medical devices that may include a cold-sprayed coating of cold-sprayed particles, the proposed medical device is made entirely of the cold-sprayed material, or includes a bulk, structural, portion thereof that is made entirely of the cold-sprayed material. A structural portion is a portion of the medical device that by itself provides for example support to tissues when implanted in the body or that maintains integrity of the device. In some embodiments, the proposed medical devices are made entirely of metal particles.

It should be noted that the terminology “particles” relates to elements that are smaller than most (or all) of the details of the structure to manufacture. In the case of a stent, the particles have a size that is smaller than the thickness of the stent struts, so that each strut includes many particles. Bioresorption is not achieved by sudden detachment of large elements from the stent, but by gradual disintegration of the stent struts.

It should be noted that this approach is to be contrasted with, for example, the medical devices described in US Patent Application Publication 20100249927 of Yang et al. published on Sep. 30, 2010, in which all the particles have a centre of a first material and a coating of a second material. Such devices are not bioresorbable and the galvanic cells formed are used to generate a current to enhance antiseptic properties of the devices. In these devices, all the particles forming the stent have the same composition. In contrast, the proposed bioresorbable material stent includes two different types of particles. Also, the proposed material and devices manufactured therewith differ greatly from the stents described in U.S. Pat. No. 7,854,958 in the name of Kramer issued Dec. 21, 2010 in which a single material is cold-sprayed to obtain a porous stent. Once again, the devices described in this patent are not bioresorbable. In addition, due to their porous nature, they are relatively fragile.

Also, particulate materials, such as those manufactured using cold spray, are conventionally used to prevent corrosion and wear. As such, only one material is used, often to form a coating on the object to protect. It is contrary to the conventional wisdom in this field to instead promote galvanic corrosion within the material. Also, other techniques described herein, including folding laminates or braiding and weaving wires of different compositions do not require the cold spray process and may use any suitable conventional metal wires and films.

The anodic and cathodic particles form a plurality of galvanic pair cells or structures. The proposed mechanism of bioresorption for the new biodegradable material is similar to the concept of sacrificial anode used in the ship industry to protect boat hulls from corroding, but with the distinction that corrosion of the anode is a desired effect that will lead to loss of cohesion of the proposed material at a desired controlled rate. Two (or more) dissimilar powders are thoroughly mixed prior to the cold spray. Anodic particles (less noble metal) and cathodic particles (more noble metal) are substantially homogeneously mixed using known methods. When in the presence of an electrolyte, current will flow between the anodic and cathodic particles in the cold-sprayed material, which will lead to corrosion of the anodic material, which, in turn, will allow resorption of the medical devices manufactured using the proposed material. In typical embodiments, this resorption will occur substantially homogeneously.

More generally speaking, there is proposed an intermixed particulate material comprising cathodic particles and anodic particles bound, or amalgamated, to each other, the anodic particles being made of an anodic material and the cathodic particles being made of a cathodic material, the anodic and cathodic materials forming a galvanic couple. While bioresorption is a useful property of the proposed material, in alternative embodiments, the proposed material is manufactured such that bioresorption proceeds at such a small rate that it does not occur during the lifetime of the patient. In this case, it is the other properties of the proposed material, such as mechanical properties, that are advantageously used. Typically, when the manufacturing process described hereinbelow is used, the cathodic and anodic particles are randomly and substantially homogeneously dispersed in the bioresorbable material. However, it is possible to have non-random distribution of the anodic and cathodic particles, for example if self-assembling materials are used.

In the case in which a bioresorbable stent is manufactured, the stent includes the bioresorbable material. The stent may be entirely made of the bioresorbable material, or the stent may also include a non-bioresorbable portion made of a non-bioresorbable material, such as pure stainless steel, among other conventional possibilities. In the latter embodiments, a portion of the stent remains in the patient after the remainder of the stent has been resorbed. For example, the non-resorbed portion could include a marker usable to locate the stent implantation site after most of the stent has been resorbed, for example for follow up exams. In another example, the non-resorbed portion could be a stent graft anchoring, a valve anchoring, a clip or a suture that anchors another structure. In these embodiments, the other structure remains in place even after a portion of the stent, which was useful to support the vessel during a healing process, has been resorbed.

When the proposed material is used to manufacture a medical device, the anodic and cathodic materials or a combination of them are biocompatible, typically during the entire life cycle of the device. Typically, the anodic and cathodic materials are metallic.

In some embodiments of the invention, the anodic material is selected from the group consisting of iron, iron-alloys and vanadium, and the cathodic material is selected from the group consisting of cobalt-chromium alloys, stainless steel, tantalum, titanium and platinum-steels. In more specific embodiments of the invention, the anodic material and cathodic material are selected from the group of couples consisting of iron/stainless steel and iron-tantalum. However, other possibilities are within the scope of the invention.

The anodic and cathodic particles are in some embodiments from about 1 μm to about 30 μm in average size, which is advantageous in the manufacture of devices including sub-millimeter sized elements. Average size is defined as a mean value in a Gaussian distribution of sizes, as assessed using microscope imaging. For example, the anodic and cathodic particles are produced by melting the anodic and cathodic materials and pouring the molten materials on a spinning wheel, which creates a rain of small droplets of molten material. Cold water is sprayed afterwards on the resulting droplets, which solidifies the anodic and cathodic particles. The resulting shape is substantially spherical and size refers to the diameter of the particles. In another example, the anodic and cathodic particles are created by grinding the anodic and cathodic materials in bulk form to make powders. The resulting particles are irregular. These irregular particles are then heated, which again produces substantially spherical anodic and cathodic particles, and size refers again to the diameter of the particles.

The anodic and cathodic particles each include grains. The grains typically have much smaller dimensions than the particles. In some embodiments of the invention, the grains are about 1 μm or less in average size. In other embodiments, the grains are about 4 μm or less in average size. In yet other embodiments, the grains are about 10 μm or less in average size. Relatively small grain size promotes ductility of the devices manufactured using the proposed devices, which is often advantageous.

When a cold spray process is used, it is useful in some embodiments to have anodic and cathodic particles with some properties that are similar to promote good material properties. For example, the anodic and cathodic materials have bulk specific weights that differ by about 50% or less, and in more specific examples, the anodic and cathodic materials have bulk specific weights that differ by about 20% or less. This promotes good mixing of the particles to ensure homogeneous and random distribution of the anodic and cathodic particles in the proposed material. The bulk specific weight refers to the specific weight of the material in bulk form, not to the specific weight of the material in particulate powder form. In the context of this document, “differing by X %” is to be interpreted as meaning that the largest property is X % larger than the smallest property. For example, a material having a specific weight of 2 g/cm³ and a material having a specific weight of 3 g/cm³ differ in specific weight by 50%.

In some embodiments of the invention, the anodic and cathodic materials have hardnesses that differ by about 50% or less, and in more specific examples, the anodic and cathodic materials have hardnesses that differ by about 20% or less. This promotes good adhesion between the particles.

One could hypothesize that a ratio of 1:1 w/w between the number of cathodic and anodic particles would be desired so that the same number of electron receiving and releasing particles are provided. While this ratio can provide bioresorbable materials, it was found that, surprisingly, a predetermined ratio of about 4:1 w/w or more in the anodic particles with respect to the cathodic particles provides faster corrosion, which is advantageous in some situations. It is believed that in more extreme examples, a predetermined ratio of about 8:1 w/w or more in the anodic particles with respect to the cathodic particles, or even a predetermined ratio of about 20:1 w/w or more in the anodic particles with respect to the cathodic particles is also achievable while preserving the bioresorption properties.

In some embodiments, the proposed material is a dynamically annealed material in which the material has been heated at a time varying temperature to correct defects within the particles without promoting large grain growth. This preserves ductility while increasing hardness. However, other types of annealing are possible to achieve suitable grain size.

In addition to manipulation of the many variables involved in the structure of the proposed material, such as selection of anodic and cathodic materials and their proportions, dimensions of particles, manufacturing conditions and annealing conditions, in some embodiments additional particles are present in the material to control bioresorption rates.

More specifically, the medical device manufactured, such as a stent, is bioresorbable at a predetermined rate. Rate may be defined as the rate of mass lost percentage, a corrosion rate in mm/unit of time, or in any other suitable manner. To that effect, the anodic particles, cathodic particles and predetermined ratio between the two are selected such that the stent is bioresorbable at the predetermined rate due to galvanic corrosion between the anodic and cathodic materials. To guide the selection of particles, galvanic corrosion theories that relate the current density between two dissimilar materials and their degradation rates may be used. In those theoretical descriptions, an equation for galvanic corrosion is derived based on the corrosion current density of uncoupled alloys. This allows the quantification of the corrosion rates based on potentiodynamic current measurements and permits an estimate of the mass depletion rates based on these current measurements. Examples of such theories are found in “Electrochemical Theory of Galvanic Corrosion”, John W. Oldfield, ASTM STP 978 H. P. Hack Ed American Society for Testing and Materials, Philadelphia, 1988, p. 5-22 and “A Theoretical approach to galvanic corrosion, allowing for cathode dissolution”, S. Fangteng, E. A. Charles, Corrosion Science 28(7):649-655, 1988. These two documents are hereby incorporated by reference in their entirety.

In some embodiments of the invention, the bioresorbable material further includes rate control particles made of a rate control material and dispersed in the bioresorbable material. The rate control particles affect the galvanic corrosion to change the predetermined rate in accordance with a predetermined rate change. For example, the rate control particles increase the predetermined rate by increasing electron transport between the anodic and cathodic particles. In another example, the rate control particles decrease the predetermined rate by decreasing electron transport between the anodic and cathodic particles. Specific examples of rate control particles that increase the predetermined rate include salts (such as calcium, potassium and sodium salts), acids and solid electrolytes. Specific examples of rate control particles that decrease the predetermined rate include chromium, polymer, silicon, ceramics, dielectrics and oxides.

With the cold spray materials, the corrosion rate can be adjusted (decreased or increased) using specific thermal treatments. Indeed, with certain mixtures (Fe-316L), it was observed that the corrosion can be accelerated by increasing the temperatures of the heat treatment (higher temperatures generate higher corrosion rates).”

Typically, the proposed material is substantially non-porous. For example, this is achieved by having a material that has a porosity of about 0.2% or less.

An example of a manner of manufacturing a stent is given hereinbelow with reference to FIG. 1. However, other devices can be similarly manufactured using the proposed material. More specifically, FIG. 1 illustrates a method 10 for manufacturing a bioresorbable stent. The method begins at step 12. Then, at step 14, an anodic powder including anodic particles made of an anodic material and a cathodic powder including cathodic particles made of a cathodic material are provided. The anodic and cathodic materials form a galvanic couple, as described in greater detail hereinabove. Then, at step 16, the method includes mixing the anodic and cathodic powders together in the predetermined ratio to obtain a mixed powder. Afterward, at step 18, the method includes cold spraying the mixed powder on a substrate, for example a steel substrate, to obtain a bioresorbable material. In some embodiments of the invention, the substrate is substantially planar, but other shapes are possible. In some embodiments of the invention, at step 20, the material is annealed. In both cases, whether there is annealing or not, the method then proceeds to step 22 of processing the bioresorbable material to form the bioresorbable stent and ends at step 24. When it is desired to manufacture the material only for future use, step 22 is omitted from the method 10. The proposed bioresorbable materials manufactured are complex multi-scale structures (nano-size grains, micro-size particles, and macro-size layering). Dedicated thermal treatment, annealing, retains the multi-scale structure while improving the ductility for stent usage.

In some embodiments of the invention, step 14 also includes providing a bioresorption rate control powder including rate control particles made of the rate control material. In these embodiments, step 16 also includes mixing a rate control quantity of the bioresorption rate control powder with the anodic and cathodic powders to obtain the mixed powder.

Step 22 may be performed in many possible manners. A non-exclusive but advantageous manner of performing step 22 is to first take a slice of a predetermined thickness of the bioresorbable material, removing the substrate, and then shape the slice to form the bioresorbable stent. In some embodiments, the slice is taken parallel to the substrate, so that the slice includes only the bioresorbable material, and no part of the substrate. The slice includes substantially opposed slice first and second side edges extending between substantially opposed ends of the slice. The thickness of the slice is about the thickness of the stent after it has been manufactured. For example, taking the slice of the predetermined thickness of the bioresorbable material includes cutting the slice with an electrical discharge machine (EDM). It has been found that slices of less than 100 μm in predetermined thickness are obtainable, which allows manufacturing relatively small stents.

In a first example, shaping the slice includes folding the slice to form a cylinder so that the slice first and second side edges are substantially adjacent to each other and welding the slice first and second side edges to each other. In a second example, shaping the slice includes embossing the slice to form a half-cylinder and welding a similar half-cylinder thereto to form a complete cylinder.

Typically, shaping the slice to form the stent includes forming a substantially cylindrical stent blank and cutting out portions of the stent blank to define stent struts. Typically, cutting out portions of the stent blank includes laser cutting the portions of the stent blank under conditions maintaining the stent blank under an annealing temperature of the anodic and cathodic materials, for example using a so-called “cold” laser, or femtosecond laser. However, in alternative embodiments, the portions of the flat material are first cut out and the resulting flattened stent is then folded in a cylindrical shape.

In another variant, step 22 is performed using a relatively thicker bioresorbable material and processing the bioresorbable material to form the bioresorbable stent includes cutting a cylinder in the bioresorbable material and emptying the cylinder to form the stent blank. This variant advantageously removes the need for welding.

A specific example of this variant is illustrated in greater details in FIGS. 7A to 7H. This example uses electrical discharge machining (EDM) to machine a stent blank. It should be mentioned that the use of EDM in the present case is highly unconventional. Indeed, we propose machining an amalgamated material including particles of two different compositions with EDM. Indeed, EDM is typically performed under a single set of parameters that would work best on a particular metal or alloy. In the present case, the amalgamated material includes two different metallic phases in the same structure. It would not be expected cutting the amalgamated material with the EDM method would work since it would typically require two different parameters since we are dealing with two metals at once.

Also, in some embodiments, the EDM method is set-up to use oil-based dielectric fluids (since aqueous-based would try to corrode the amalgamate prematurely). These oil-based dielectric fluids are typically at high speed or pressure to promote high convection rates since the amalgamated material is sensitive to heat. EDM does create heat, but it quickly dissipates if we used forced convection from a high speed dielectric fluid flow.

Since EDM is a contactless method of cutting stent blanks, EDM will only minimally, if at all, mechanically affect the microstructure of the amalgamated material due to some mechanical deformation as it would occur with machining or with rolling methods. So, from this perspective EDM advantageous to preserve as much as possible the metallic microstructure of the different metallic phases, or preserve the grain sizes after a certain heat treatment due to its contactless nature.

More specifically, in this proposed variant, a mixed powder including anodic particles made of a metallic anodic material and cathodic particles made of a metallic cathodic material are provided, the anodic and cathodic materials forming a galvanic couple. The cathodic and anodic particles are as described above. As seen in FIG. 7A, the variant uses a substrate 100. For example, the substrate 100 is substantially plate-shaped and metallic.

Then, as seen in FIG. 7B, the mixed powder is cold-sprayed on the substrate 100 to obtain an amalgamated material 102 including the anodic and cathodic particles. The amalgamated material 102 is illustrated in the drawings as a sheet of substantially constant thickness thereacross. In such cases, a plurality of stent blanks could be manufactured in a grid-like fashion out of the amalgamated material 102. However, in other embodiments, only a portion of the amalgamated material is relatively thick and the stent blanks are manufactured only in this section.

In some embodiments, as seen in FIG. 7C, the amalgamated material 102 is removed from the substrate 100. This can be done in any suitable manner, for example using wire EDM or any of the relevant methods mentioned hereinabove. If desired, the amalgamated material 102 may then be annealed. However, in some embodiments, no annealing is performed, or only a resulting stent blank is annealed.

In a specific example, the amalgamated material 102 is annealed under conditions resulting in grains of the anodic and cathodic materials in the anodic and cathodic particles to remain below about 1 μm, 4 μm or 10 μm in average size. Typically, the amalgamated material is annealed at a temperature below a sintering temperature of the amalgamated material 102. For example, the amalgamated material 102 is annealed at a temperature between 70% and 90% of a melting temperature of a lowest melting temperature material selected from the anodic and cathodic materials.

For example, if the cathodic material is stainless steel and the anodic material is iron, the amalgamated material 102 may be annealed at an annealing temperature of between 800° C. and 1400° C. for an annealing duration of 30 minutes to 4 hours. In a more specific example, the annealing temperature is between 1100° C. and 1300° C. and the annealing duration is between 1 and 3 hours. The amalgamated material may be brought from room temperature to the annealing temperature at a predetermined heating rate. For example, the predetermined heating rate is between about 100° C./hr and about 400° C./hr. In a very specific example, the predetermined heating rate is about 250° C./hr. Also, the amalgamated material may be brought from the annealing temperature to the room temperature at a predetermined cooling rate, for example between about 100 and about 400° C./hr. In a very specific example, the predetermined cooling rate is about 250° C./hr.

Afterwards, a substantially tubular stent blank 104, seen in FIG. 7G, is made of the amalgamated material by machining the amalgamated material using electrical discharge machining (EDM). Then, selected portion of the stent blank 104 are removed to form the stent 114, seen in FIG. 7H, for example by defining stent struts. A large variety of methods may be used to that effect, for example using a picosecond or femtosecond laser, among many possibilities.

The stent blank 104 defines a longitudinally extending stent blank passageway 106. In some embodiments, the stent blank passageway 106 is formed in the amalgamated material before a peripheral surface 108 of the stent blank is machined.

As seen in the sequence of FIGS. 7D to 7F, one specific manner of forming the stent blank passageway 106 includes forming a pilot hole 110, seen in FIG. 7D, in the amalgamated material 102, inserting an EDM wire 112 in the pilot hole 110, as seen in FIG. 7E, and enlarging the pilot hole 110 to a predetermined diameter using wire EDM to form the stent blank passageway 106, as seen in FIG. 7F. The pilot hole 110 may be formed using EDM or simply drilled. Indeed, as the pilot hole 110 is surrounded by a large mass of the amalgamated material, and since the material surrounding the pilot hole 110 is removed afterwards, mechanical drilling of the pilot hole 110 will not unduly affect the portion of the amalgamated material that will form the stent blank 104. Once the stent blank passageway is formed, wire EDM can be used to form the stent blank peripheral surface 108.

After the above steps, conventional stent manufacturing steps are performed, such as crimping the stent on a balloon for implantation. It should be noted that any other type of medical device that needs to be resorbed or degraded once implanted may also be machined using EDM from the amalgamated material.

To use the stent in a patient, first, a desired resorption rate of the bioresorbable stent is determined by a clinician. This determination depends on clinical and biological criteria. Then, the method of use includes selecting a patient stent from a set of predetermined stents, the patient stent having the desired resorption rate when implanted in the patient. Afterward, the patient stent is implanted in the patient. The proposed stent has been found to be advantageous for use in coronary and pulmonary blood vessels, but other uses are possible. For example, the proposed stent can be used in hepatic, biliary, and peripheral vessels. Also, the proposed stent can be used in non-blood carrying vessels. Finally, the method further comprises resorbing the stent in the patient at the desired resorption rate.

The ductility of the cold sprayed bioresorbable material typically needs to be improved with thermal treatment. Various treatments are possible to optimize the final desired mechanical properties. After cold spraying, the bioresorbable material is in a highly work-hardened state. Annealing is usually performed to restore the structure to a re-crystalized state, which is often preferable for various mechanical properties. Furthermore, control of annealing parameters enables control of the mechanical properties of the material. Annealing can be performed isothermally by heating the material, for example in an electric resistance furnace in air followed by air cooling. However, one has to ensure that the thermal treatment preserves the micro and the nano structures of the sprayed materials.

EXAMPLE

FIGS. 2A to 2C illustrate at various scales a stent manufactured using the method 10. This stent is made of cold sprayed iron particles and stainless steel particles, both having an average size of about 5 μm, in a 4:1 w/w ratio and has an outer diameter of 8 mm with 200 μm thick struts. No annealing was performed. FIG. 6 illustrates the microstructure of the material used to manufacture the stent, after the cold spraying step.

FIG. 3 illustrates corrosion rate of various bioresorbable materials manufactured using the method 10, without step 22. The particles were iron and stainless steel (316L). Curves of corrosion as a function of time per unit area are shown for the various proportions. FIG. 4 shows this data in a different form where the corrosion rate is plotted. Finally, FIG. 5 illustrates the polarization graphs used to investigate corrosion rate in an alternative manner. The corrosion rates were 0.215 mm/yr for pure iron, 0.18 mm/yr for 316L/iron in a 1:4 ratio, 0.1128 mm/yr for 316L/iron in a 1:1 ratio, and 0.107 mm/yr for 316L/iron in a 4:1 ratio.

In other embodiments, wires, sheets, plates, cylinders or tubular forms of dissimilar materials are used to manufacture other bioresorbable medical devices, such as stents or scaffolds. For simplicity, reference is made hereinbelow to a stent, which includes as mentioned hereinabove scaffolds, but other types of medical devices may also be manufactured using similar structures and methods.

In a first variant, the stent includes an anodic material in filament form and a cathodic material in filament form. The stent may be made with long filaments that are for example braided together, of with shorter filament segments that form a fabric, among other possibilities. For example, the filaments have about between 1 and 10 μm in diameter, and are braided to make wires of between 50 and 200 μm in diameter. In other embodiments, the filaments and/or wires may have larger or smaller diameters. The stent is therefore made biodegradable, or bioresorbable, by braiding different filaments, for example micro-wires, of dissimilar metals. As a result, the wire (which for example defines stent struts) exhibits a micro-galvanic corrosion and thus biodegrades in presence of an electrolyte (such as, non-limitingly, blood plasma).

The resulting braided wire (with predetermined arrangements and predetermined ratios of anodic and cathodic wires) exhibits galvanic degradation at the contact areas between the two dissimilar metals. By using two metals that fully degrade (like mild steels, for example, but of different compositions) this results in a fully degradable wire. However, stents that do not fully degrade, or in other words that are only partially resorbed, are also within the scope of the invention. The wire can then be shaped in any predetermined configuration (and possibly micro-welded) to achieve a desired stent design and dimensions. It is also possible to perform heat treatments to improve the bioresorption properties of the wires and improve bonding.

The anodic and cathodic materials are typically metallic and form a galvanic couple. The anodic and cathodic materials are distributed in the stent so that the anodic and cathodic materials contact each other at a plurality of junctions. The cathodic and anodic materials usable in this variant are the same that are usable in the cold-sprayed material described above. Mild steel is also usable both in the presently described variants and in the cold-sprayed material. Bioresorption of the stent is promoted by galvanic corrosion between the anodic and cathodic materials at the junctions.

More specifically, in a specific embodiment, at least one anodic filament made of the anodic material and at least one cathodic filament made of the cathodic material are braided together in a wire, the wire including at least some of the plurality of junctions. The wire can then be folded in a conventional manner to form a wire or coil stent, or a few similar wires can be used to form the stent. Wire, or coil, stent are known in the art. For example, and non-limitingly, such stent are similar to the stent illustrates in U.S. Design Pat. No. 553,747 issued Oct. 23, 2007, to Cornova Inc., the contents of which is hereby incorporated by reference in its entirety.Typically, most of the junctions may be formed within the wire, with only a small number of them formed where the wire intersects itself. Micro-welding may be used an locations where the wire intersects itself if needed. FIG. 8 illustrates braiding of four anodic filaments 202 (in black) and four cathodic filaments 204 (in white) together to form a wire 200. However, any suitable number of anodic and cathodic filaments is usable, including less and four and more than four. Also, the numbers of anodic and cathodic filaments don't need to be equal.

In some embodiments, the anodic and cathodic filaments are also braided with a carrier filament. The carrier filament may be metallic or not and made of the anodic material, cathodic material or of a material that differs from the anodic and cathodic materials. For example, the carrier filament is made of a bioresorbable polymer or of a suitable metal. The carrier filament may be of a larger diameter than any of the anodic and cathodic filaments. Larger filaments allow more contact between the filaments as more turns of the smaller filaments around the larger filament can be made. For example ratios of the diameters of the anodic, cathodic and carrier filaments may vary from about 0.1 to about 10. In some embodiments, the anodic and cathodic filaments have different pitches relative to the wire. This varies the amount of contact between dissimilar materials and also allows varying the relative quantity of the anodic and cathodic materials, which all affect the bioresorption rate of the stent.

Manufacturing of a wire as described above is schematically illustrated in FIG. 9. The wire 300 includes one anodic filament 302, one cathodic filament 304 and one carrier filament 306, each provided from a respective bobbin 312, 314 or 316. The anodic, cathodic and carrier filaments 302, 304 and 306 are freely removable from the bobbins 312, 314 and 316, which are free to axially rotate. The bobbins 312, 314 and 316 are mounted to a carousel 308 rotable about the longitudinal axis 310 of the wire 300. Control of the pitch of the anodic, cathodic and carrier filaments 302, 304 and 306 about the wire 300 is performed by controlling the angular velocity of the carousel 308, the speed at which the anodic, cathodic and carrier filaments 302, 304 and 306 are drawn (by pulling on the wire 300) and by selecting appropriate distances between the bobbins 312, 314 and 316 and the longitudinal axis 310, which varies the angle θ between the anodic, cathodic and carrier filaments 302, 304 and 306 and the longitudinal axis 110. For example the angle θ varies from about 0 degrees to about 89 degrees. Other techniques known in the textile and cable manufacturing industries are also usable to manufacture the wire 300. Changing the angle θ allows also to adjust the contact areas between the threads to achieve different degrees of galvanic corrosion.

In other variants, tubular stent blanks, similar to the stent blank 104 are first manufactured as described below, and the stent is then crated by removing portions of the stent blank to create stent struts and other stent structures, for example using laser systems. The tubular stent blank can be manufactured from one or more sheets of material 400, as seen in FIG. 10A. Such sheets 400 are described below in greater details. When the sheet 400 is of sufficient thickness, the sheet 400 can be rolled to form a cylindrical structure and the two sheet edges 402 and 404 that are then adjacent to each other can be secured to each other, for example through welding, as illustrated in the sequence of FIGS. 10B and 10C. In other embodiments, when the sheet 400 is too thin, multiple sheets 400 can be rolled on top of each other, as illustrated in FIG. 10D to form a tubular structure. The multiple sheets 400 can be adhered to each other in any suitable manner, for example through sintering. In yet other embodiments, the sheet 400 is rolled in a spiral to form the tubular structure, as seen in FIG. 10E, followed for example by sintering.

The sheet 400 may be manufactured using many different techniques. In a first example, illustrated in FIG. 11, a plurality of anodic filament segments 502 made of the anodic material and a plurality of cathodic filament segments 504 made of the cathodic material are weaved together in a fabric 500. The anodic filament segments 502 may be disjoint from each other or part of longer filaments folded over themselves. The same applies for the cathodic filament segments 504. The fabric 500 includes at least some of the plurality of junctions 506. For example, the anodic filament segments 502 are substantially parallel to each other in the fabric 500 and the cathodic filament segments 504 are substantially parallel to each other in the fabric 500. In a specific example, the anodic filament segments 502 are substantially perpendicular to the cathodic filament segments 504. In other embodiments, anodic and cathodic filament segments 502 and 504 are both present in the rows and in the columns of the fabric 504. Weaving may be performed using any suitable technique and any suitable weaving pattern may be used. As with the above-described variants, the diameter of the cathodic and anodic filament segments 502 and 504 may differ from each other, or within each type of segment. Multi-weaved offset layer are also usable.

In yet other embodiments, as seen for example in FIG. 13, one of the anodic and cathodic materials, for example the anodic material, forms a base grid 600 defining a plurality of grid apertures 602 and the other one of the anodic and cathodic materials, for example a cathodic filament 604 is crocheted into the base grid through the apertures 602 using a suitable head 606. The base 600 grid may be created by weaving together the selected one of the anodic and cathodic materials, similarly to the fabric 500, but loosely enough to create the grid apertures 602. In other embodiments, the base grid 600 is manufactured by removing material from a plate. Any other suitable method is also usable to manufacture the base grid 600.

The cathodic and anodic materials may be in the form of filaments having a substantially constant diameter therealong, as illustrated in FIG. 8 for example, or may be in a beaded filament form, as seen in FIG. 12 for the filament 700. Beaded filament 700 may increase the contact area between the anodic and cathodic materials. The beads of the filament 700 may extend continuously from each other, or may be separated from each other by segments of constant diameters.

In the sheets described hereinabove, the cathodic and anodic materials may be sintered or otherwise thermally adhered to each other. In other embodiments, only mechanical forces, that is tension, friction and normal forces, hold the sheet together so that no welding, sintering or other treatment is required to manufacture the sheet. In such embodiments, the cathodic and anodic filaments are under tension and the junctions are created due to normal forces between the filaments at locations where the filaments intersect. The cathodic and anodic materials may have different or similar diameters, similarly to the braided variant described above. Also, a total length of the anodic material in the stent, that is a total sum of the length of all filament or filament segments of the anodic material, may be similar or may differs from a total length of the cathodic material in the stent.

In yet another variant, the sheet 400 is manufactured by laminating the anodic and cathodic materials on top of each other. For example, as seen in FIG. 14, one of the anodic and cathodic materials is provide in the form of a thin sheet 800. The thin sheet has for example a thickness between 1 and 10 microns. Then, a suitable process, such as plasma vapor deposition (PVD), among others, is used to form a coating 802, also having a thickness of for example between 1 and 10 microns, on the sheet 800 with the other one from the anodic and cathodic materials. To form the stent, the resulting coated sheet 804 is processed to create a thicker sheet including a plurality of layers alternating between cathodic layers and anodic layers, thereby forming alternating galvanic couples promoting galvanic corrosion between the anodic and cathodic layers. In such embodiments, all the cathodic layers are made of a same cathodic material and all the anodic layers are made of a same anodic material. The anodic and cathodic layers may have similar or different thicknesses. The coated sheet 804 can then be rolled into a spiral to form a cathodic spiralling sheet made of the cathodic material an an anodic spiralling sheet made of the anodic material and parallel to the cathodic spiralling sheet. In other embodiments, the coated sheet 804 is folded in any suitable manner. Resulting in the cathodic and anodic layers to alternate in the folded sheet. The sheet can then be rolled to form a stent blank, as described above.

In this approach, the micro-galvanic reaction is induced by layering micro-foils of dissimilar metals in alternate manners. After the lamination, the structure is for example heat treated to ensure proper bonding, for example at between 500° C. and 800° C. Following the heat treatment, the laminated structures is folded to expose the dissimilar sides to each other (in order to induce the galvanic couple). Different folding can be considered, some of which are illustrated in FIGS. 15A to 15F which illustrate respectively, a rri-fold, a roll fold, a gate fold, an accordion fold, a double parallel fold and a flip fold. It should be noted that in some folds, the same metal is folded over itself, but alternating layers of different compositions are nevertheless created. The laminated sheet 804 can be folded repeatedly using the same folding method, or by mixing the folding method, to form thicker sheets.

Other suitable manners of manufacturing a layered structure as defines above are also within the scope of the invention, such as, for example, depositing multiple alternating layers of anodic and cathodic materials using plasma deposition, among others.

All the above structures allow to manufacture macro scale medical devices that present complete bioresorption by having galvanic couples at the micro scale (for example 1 to 10 μm order). The micro scale may be 0-dimensional (as in the particulate material), 1-dimensional (using wires) or 2-dimensional (using folded sheets). Using proper materials, dimensions and heat treatments allows for providing a predetermined, controlled, degradation rate.

Although the present invention has been described hereinabove by way of preferred embodiments thereof, it can be modified, without departing from the spirit and nature of the subject invention as defined in the appended claims. 

1. A bioresorbable stent, comprising: an anodic material in filament form and a cathodic material in filament form, the anodic and cathodic materials being metallic and forming a galvanic couple, the anodic and cathodic materials being distributed in the stent so that the anodic and cathodic materials contact each other at a plurality of junctions; wherein bioresorption of the stent is promoted by galvanic corrosion between the anodic and cathodic materials at the junctions.
 2. The bioresorbable stent as defined in claim 1, wherein at least one anodic filament made of the anodic material and at least one cathodic filament made of the cathodic material are braided together in a wire, the wire including at least some of the plurality of junctions.
 3. The bioresorbable stent as defined in claim 2, wherein the anodic and cathodic filaments are also braided with a carrier filament.
 4. The bioresorbable stent as defined in claim 3, wherein the carrier filament is metallic.
 5. The bioresorbable stent as defined in claim 3, wherein the carrier filament is made of a material that differs from the anodic and cathodic materials.
 6. The bioresorbable stent as defined in claim 3, wherein the anodic and cathodic filaments have different pitches relative to the wire.
 7. The bioresorbable stent as defined in claim 2, wherein the bioresorbable stent is a wire stent made of one or more of the wires.
 8. The bioresorbable stent as defined in claim 1, wherein a plurality of anodic filament segments made of the anodic material and a plurality of cathodic filament segments made of the cathodic material are weaved together in a fabric, the fabric including at least some of the plurality of junctions.
 9. The bioresorbable stent as defined in claim 8, wherein the anodic filament segments are substantially parallel to each other in the fabric and the cathodic filament segments are substantially parallel to each other in the fabric, the anodic filament segment being substantially perpendicular to the cathodic filament segments.
 10. The bioresorbable stent as defined in claim 1, wherein one of the anodic and cathodic materials forms a base grid defining a plurality of grid apertures and another one of the anodic and cathodic materials is crocheted into the base grid through the apertures.
 11. The bioresorbable stent as defined in claim 10, wherein at least one of the cathodic and anodic materials are in beaded filament form.
 12. The bioresorbable stent as defined in claim 11, wherein both the cathodic and anodic materials are in beaded filament form.
 13. The bioresorbable stent as defined in claim 1, wherein the cathodic and anodic filaments are under tension and the junctions are created due to normal forces between the filaments at locations where the filaments intersect.
 14. The bioresorbable stent as defined in claim 1, wherein the cathodic and anodic materials are sintered to each other.
 15. The bioresorbable stent as defined in claim 1, wherein the anodic material is selected from the group consisting of iron, iron alloys, mild steel and vanadium and the cathodic material is selected from the group consisting of cobalt-chromium alloys, stainless steel, mild steel, tantalum, titanium and platinum-steels.
 16. The bioresorbable stent as defined in claim 1, wherein the anodic material and cathodic material are selected from the group of couples consisting of iron/stainless steel, two different mild steels and iron/tantalum.
 17. The bioresorbable stent as defined in claim 1, wherein the cathodic and anodic materials have different diameters.
 18. The bioresorbable stent as defined in claim 1, wherein a total length of the anodic material in the bioresorbable stent differs from a total length of the cathodic material in the bioresorbable stent.
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 29. A method of manufacturing a bioresorbable wire, the method comprising braiding together at least two metallic filaments having different galvanic potentials.
 30. The method as defined in claim 29, wherein the two filaments are different mild steels. 31.-65. (canceled) 